The present invention is generally directed to a tissue engineered (TE) testicular prosthesis having both cosmetic and therapeutic uses.
Testicular dysfunction, characterized by either an absence of androgenic production, an absence of the testes, or both, has great medical and psychological consequences on the afflicted male population ranging from infertility and cancer to psychiatric disturbances. Causes of testicular dysfunction include chromosomal abnormalities, testicular torsion (which may be a result of inadequate connective tissue within the scrotum or trauma to the scrotum, after strenuous exercise or without an obvious cause; the incidence is higher during infancy and with the onset of adolescence) direct trauma to the testicles, diseases that affect the testicle (such as mumps orchitis and testicular cancer), and a variety of drugs. Increased risk is associated with activities that may cause constant, low level trauma to the scrotum (such as riding a motorcycle) or frequent administration of a drug known to affect testicular function (such as heavy marijuana use or taking some prescription medications). Thus, testicular dysfunction can result at the time of fetal development, adolescence and during the adult years.
During fetal development, the fetal testes are formed within the abdominal cavity in the region where the kidneys are normally located in adults. They descend into their normal scrotal position shortly before birth. The prevalence of undescended testes (cryptorchidism) is 3.4% in full-term infants and as high as 30% in premature infants. The testes often descend after birth, and the prevalence of cryptorchidism by one year of age is down to 1%. Current practice is to surgically correct undescended testes at around age one year. The main reason for bringing the testes down early is to preserve future fertility. Testicular atrophy may be present due to a primary abnormality of the testis or due to damage incurred during surgery. A testicular prosthesis could be inserted for cosmetic reasons, but the undescended testicle may have to be removed to achieve the desired xe2x80x9cnormalxe2x80x9d result. This undescended testes may be producing hormones and be worth sparing. However, the risks of inserting a testicular prosthesis are minimal and consist of infection (around 2%) and bruising. Physicians frequently recommend that a testicular prosthesis be placed early in life to prevent shrinkage of the scrotum which can occur when the sac is empty, and allow for normal psychological development through the patient""s early years.
In addition, there is an association between cryptorchidism and testicular cancer. Approximately 10% of testicular tumors arise from an undescended testis, and the risk of malignancy in an undescended testis is thought to be 35-fold higher than for a normal descended testis. The best way to detect testicular cancer is by palpation. Thus, another reason for surgically correcting cryptorchidism is to allow the patient to easily perform monthly self-examination. Yet despite this increased risk, the annual risk of malignancy is estimated to be only one in 2,550 cases. Moreover, the risk of death from removal of the testis is higher than the risk of testicular cancer in patients over 32 years of age.
To date, testicular prosthesis have been of solid material or have been filled with a soft silicone elastomer or a silicone gel. See xe2x80x9cThe Why and How of Synthetic Replacement Testiclesxe2x80x9d by Joseph Ortenberg. M.D. and Robert G. Kupper, M.D. in Contemporary Urology. October 1991. pp 23-32. Moreover, no testicular implants have been sold in the U.S. since 1995, when the FDA called for a pre-market approval application on these devices in fear of harmful effect of silicone. As a result, Silicone Gel implants are not available in the U.S., and the American Urological Association have advised against using these products. A Silicone Elastomer prosthesis may be available, and is endorsed for use by the American Urological Association. Hence, alternatives to testicular implants are very limited, leaving patients with few treatment options.
Recently, Mentor Corporation of Santa Barbara, Calif. developed a saline-filled implant which is currently awaiting the FDA approval. The Mentor testicular prosthesis approximates the weight, shape, and feel of a normal testicle. The prosthesis is available in four sizes, extra small, small, medium, and large. The implant consists of a molded silicone-elastomer shell approximately 0.035 inches thick, with a self-sealing injection site located on one end of the prosthesis. The injection site allows the surgeon to fill the implant with sterile, pyrogen-free Sodium Chloride USP solution. On the end opposite of the fill site is a silicone elastomer tab for suturing the prosthesis in place. See U.S. Pat. Nos. 6,060,639 and 5,653,757.
The prosthetic testicles that are available today have a realistic appearance but may feel foreign (hard) and cause discomfort. It is not uncommon for patients to remove the prosthesis several years later due to pain and discomfort. Because artificial testicles do not move as natural testicle do, they sometimes become fixed in peculiar positions thereby causing the scrotum to hang abnormally. Moreover, with the normal developmental growth, corresponding larger testicle sizes must be surgically replaced. With the available prosthetic options, it is often recommended to young patients to attenuate prosthetic placement as long as possible in order to reduce the number of procedures required to maintain the appropriate testicle size. This of course does not address the emotional issues associated with the artificial testicle and numerous replacement surgeries. Additionally, male patients with an absence of testes (anorchia) commonly require testicular prosthesis placement and hormone replacement treatment. Unfortunately, the currently available testicular prosthesis have no capabilities to produce and supply androgenic substances, and the several types of testosterone compounds and various modes of hormone deliver, that are currently used clinically, however, have pharmacokinetic properties that are not ideal.
The testes of male mammals, including humans, is the source of circulating androgens that are responsible for the maintenance of the secondary sexual characteristics in the male. In most species, the testes is divided into two separate compartments: the seminiferous tubules that contain the Sertoli cells, the peritubular cells and the germ cells; and the interstitial compartment that contains the Leydig cells, macrophages, lymphocytes, granulocytes and the cells composing the blood, nerve and lymphatic structures. Leydig cells are interspersed between the various coils of the seminiferous tubules, and are responsible for the production of androgens or male sex hormones.
The Leydig cells, located in the interstitial compartment and comprising approximately 2-3% of the total testicular cell number in most species, are the only testicular cells capable of the first two steps in steroidogenesis; i) the conversion of cholesterol, the substrate for all steroid hormones, to pregnenolone: and ii) conversion of pregnenolone to progesterone. Therefore, the interstitial compartment in general, and the Leydig cells in particular synthesize virtually all of the steroids produced in the testis with testosterone being the major steroid biosynthesized.
The major stimulus for the biosynthesis of testosterone in the Leydig cell is the gonadotrophic hormone, luteinizing hormone (LH). LH is secreted from specific cells located in the anterior pituitary and it interacts with specific receptors on the surface of the Leydig cell and initiates the signal for testosterone production. Cellular events occur rapidly in response to the trophic hormone stimulation of Leydig cells, and result in the synthesis and secretion of testosterone.
Patients with testicular dysfunction require androgen replacement for somatic development. xe2x80x9cAndrogenxe2x80x9d refers to a family of male sex hormones which include, without limitation, testosterone, dihydrotestosterone, and rostenedione. Androgens such as testosterone, play a key role in the development of male sexual characteristics such as growth of the penis, muscles and beard as well as deepening of the voice.
Testosterone therapy is currently indicated for treatment of male hypogonadism, anemia, breast cancer, and hereditary angioedema. It is also being considered for treating a variety of other conditions such as male osteoporosis that appear to be mediated by androgen deficiency.
Traditional modalities for administering testosterone have include: intramuscular injection of long-acting testosterone esters such as the enanthate because testosterone itself is rapidly degraded by the liver if administered orally; oral administration of testosterone undecanoate, which provides systemically available testosterone; and subcutaneous implantation of fused testosterone pellets. However, none of these traditional modalities provides totally physiological levels or circadian patterns of testosterone and its active metabolites, dihydrotestosterone (DHT) and estradiol (E2), and long term non-pulsatile testosterone therapy may cause multiple problems, including erythropoiesis and bone density changes.
For the foregoing reasons and deficiencies of the current state of the art, there exists a need for (1) a TE testicular prosthesis that would not require periodic removal to correct for size changes, and (2) a TE testicular prosthesis that can be used therapeutically in controlled androgen replacement therapy (e.g., testosterone replacement) and long term physiological release of androgens, such as testosterone, without the side-effects encountered in the currently available treatments.
It is an object of the present invention to provide a tissue-engineered, testicular prosthesis for the purpose of replacing an absent or abnormal testicle in a male patient. It is a further object of this invention to provide a tissue-engineered testicular prosthesis that is therapeutically functional in that it would be able to satisfy the function of a normal testicle by releasing testosterone.
The prosthesis of the present invention is suited for use in male patients of all ages for whom testicular replacement is indicated either with or without the therapeutic release of testosterone, e.g., children with undescended testicles or torsion of the testicle, and adults with testicular cancer, traumatic injury or orchiectomy. The prosthesis of the present invention is especially suited for use in infants or young children.
It is yet another object of the present invention to provide a TE testicular prosthesis capable of providing a controlled androgen replacement therapy and long term physiological release of androgen, such as testosterone, in males in need thereof.
In one aspect of the invention, the TE testicular prosthesis for implanting within a patient comprises a scaffold comprising a biodegradable polymer scaffold having a substantially elliptical body in longitudinal cross-section replicating the shape of a testicle and a substantially circular cross-section in transverse cross-section, the biodegradable scaffold defining an interior and an exterior of the prosthesis, and the scaffold being seeded with disassociated chondrocytes or Leydig cells, or both chondrocytes and Leydig cells. In one embodiment of the invention, the biodegradable polymer scaffold has an inner interconnected mesh network.
The use chondrocytes as a scaffold seed provides the benefit of the resulting testicle to approximate the density of the normal testicle thereby providing a more natural and comfortable feeling to the patient compare to the foreign sensation and sometimes pain that is typically caused a silicone prosthesis.
In another embodiment of the invention, the interior of the TE testicular prosthesis is filled, at least partially, with testosterone for the physiological release of the substance. The physiological release of testosterone typically continues for a time period after which the interior is refilled.
When the scaffold is seeded with Leydig cells alone or with Leydig, cells in combination with chondrocytes, the resulting prosthesis functions both cosmetically and therapeutically as a testosterone production and secretion source.
The seeded scaffold can be cultured in vitro or in vivo. Preferably the seeded scaffold is cultured in vitro prior to implantation in a host. Preferably, the culturing is for a time period sufficient for cartilaginous tissue to form.
The chondrocytes can be autologous, allogenic or xenogenic. Autologous chondrocytes are preferred. In patients lacking testicles, donor Leydig cells can be used.
The term xe2x80x9cbiodegradablexe2x80x9d, as used herein refers to materials which are enzymatically or chemically degraded in vivo into simpler chemical species. Either natural or synthetic polymers can be used to form the matrix, although synthetic biodegradable polymers are preferred for reproducibility and controlled release kinetics. Synthetic polymers that can be used include polymers such as poly(lactide) (PLA), poly(glycolic acid) (PGA), poly(lactide-co-glycolide) (PLGA). poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates and degradable polyurethanes, and non-erodible polymers such as polyacrylates, ethylene-vinyl acetate polymers and other acyl substituted cellulose acetates and derivatives thereof. PGA and PLGA polymers are preferred.
Preferred biodegradable polymers comprise a polymer selected from the group consisting of polyesters of hydroxycarboxylic acids, polyanhydrides of dicarboxylic acids, and copolymers of hydroxy carboxylic acids and dicarboxylic acids. In other embodiments the material is a synthetic polymer derived from at least one of the following monomers: glycolide, lactide, p-dioxanone, caprolactone, trimethylene carbonate, butyrolactone. In preferred embodiments, the material is selected from the group consisting of polymers or copolymers of glycolic acid, lactic acid, and sebacic acid. Polyglycolic acid polymers are most preferred. A polyhydroxyalkanoate (PHA) polymer may also be used. Preferably, the polymer biodegrades in less than 3 months, more preferably, less than 2 months.
It is a further object of the present invention to provides for therapeutic delivery of an androgenic substance, such as testosterone, using a TE testicular prosthesis comprising microencapsulated Leydig cells within the prosthesis. Microencapsulated Leydig cells enable controlled testosterone replacement therapy in addition to offering several advantages, such as serving as a semipermeable barrier between the transplanted cells and the patient""s immune system, as well as allowing for the long term physiological release of testosterone. Furthermore, microencapsulated Leydig cells are viable and are able to produce testosterone in vitro and in vivo. The microencapsulation system renders the cells non-immunogenic by employing polymers that serve as an immuno-protective layer surrounding the cell. This technology can be used to replace or supplement testosterone in patients with testicular dysfunction.
In another embodiment the Leydig cells are immortalized with telomerase or by other means before incorporation into the TE testicular prosthesis. Telomerase-immortalized human cells provide more stable, uniform cell populations for long-term gene expression.
Other aspects of the invention are disclosed infra.